Pharmaceutical compositions of phenothiazone derivatives and analogs

ABSTRACT

Phenothiazone derivatives and analogs thereof, pharmaceutical compositions and methods of treatment are disclosed. These compounds are useful as inhibitors of mammalian leukotriene biosynthesis. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders and inflammation.

CROSS REFERENCE TO RELATED APPLICATIONS

This is division of U.S. Ser. No. 786,257, filed Oct. 10, 1985, now U.S.Pat. No. 4,667,032 which is a continuation-in-part of application Ser.No. 559,471, filed Dec. 12, 1983, now abandoned, which is acontinuation-in-part of application Ser. No. 536,487, filed Sept. 28,1983, now abandoned, which is a continuation-in-part of application Ser.No. 459,924, filed Jan. 22, 1983, now abandoned.

U.S. Pat. No. 4,667,032 (Lau et al.) is incorporated herein by referencein its entirety.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the present invention is a pharmaceutical compositioncontaining a compound of the Formula I: ##STR1## wherein

X is in the 1 or 3 position and is O, S or NR wherein R is H, C₁ -C₆branched or linear alkyl, CN or phenyl;

Y is O, Se, S, SO, SO₂ or NR; and the broken line represents an opticaldouble bond between the 1 and 2 or 2 and 3 position;

R₁, R₂, R₃ and R₄ are independently selected from:

(1) hydrogen;

(2) alkyl having 1-6 carbon atoms;

(3) alkenyl having 2-6 carbon atoms;

(4) --(CH₂)_(n) M wherein n is 0-6 and M is

(a) OR₅ ;

(b) halogen;

(c) CF₃ ;

(d) SR₅ wherein R₅ is H; lower alkoxy-lower alkyl; lower acyloxy-loweralkyl; C₁ -C₆ alkyl; benzyl; phenyl or substituted phenyl wherein thesubstituents are C₁ -C₃ alkyl, halogen, CN, CF₃, COOR₆, CH₂ COOR₆,(CH₂)_(n) NR₈ R₉ wherein n is 0 to 2, C₁ -C₃ alkoxy, OH, halo-C₁ -C₆-alkyl; --(CH₂)_(m) COOR₆, wherein m is 0 to 6 and R₆ is H, phenyl, orC₁ -C₆ alkyl; CN; formyl; perfluoroalkyl; or CH₂ -R₁₂ wherein n is 0 to4, R₁₂ is C₁ -C₅ alkyl, dimethylamino or phenyl;

(e) phenyl or substituted phenyl as defined above for R₅ ;

(f) COOR₆ ;

(g) ##STR2## wherein R₁₄ is H, (CH₂)_(n) COOR₆ wherein n is 0 to 4, C₁-C₆ alkyl, CF₃, phenyl, or substituted phenyl as defined above for R₅ ;

(h) tetrazole;

(i) ##STR3## wherein R₇ is C₁ -C₆ alkyl, benzyl or phenyl; (j) --NR₈ R₉wherein R₈ and R₉ are independently selected from H, phenyl orsubstituted phenyl as defined above for R₅, C₁ -C₄ alkyl, C₁ -C₄alkylamino alkyl, or may be joined through the N to form aheterocycloalkyl or 5-8 ring atoms;

(k) --NHSO₂ R₁₀ wherein R₁₀ is OH, C₁ -C₆ alkyl, C₁ -C₆ -alkoxy, phenyl,or CF₃ ;

(l) ##STR4## (m) --SOR₁₁ wherein R₁₁ is C₁ -C₆ alkyl, phenyl orsubstituted phenyl as defined above for R₅, (CH₂)_(m) COOR₆ wherein m is1 to 6, CN, formyl or perfluoro-C₁ -C₄ alkyl;

(n) --CONR₈ R₉ ;

(o) --SO₂ NR₈ R₉ ;

(p) --SO₂ R₁₃ wherein R₁₃ is OH, C₁ -C₆ alkyl, H, phenyl or substitutedphenyl as defined above for R₅, (CH₂)_(m) COOR₆ wherein m is 1 to 6, CN,formyl or perfluoro-C₁ -C₄ alkyl;

(q) NO₂ ;

(r) ##STR5## (s) ##STR6## (t) ##STR7## (u) CN; (v) NR₁₅ R₁₆ wherein R₁₅and R₁₆ are such that HNR₁₅ R₁₆ is an essential amino acid; or

any two of R₁, R₂, R₃ and R₄ are joined (e.g. as --(CH₂)₃₋₄ --) to add afourth ring to the three ring structure, said ring having 5 or 6 carbonatoms and being saturated or unsaturated; and, T is H, halogen or CF₃.

The numbers surrounding Formula I designate the substituent positions.T, R₁, R₂, R₃ and R₄ may be positioned anywhere in the structure. As anexample of compounds with a fourth ring, compounds of Formula II may beprepared by linking two of the substituent groups; R₁, R₂, R₃, R₄ :##STR8## wherein Z may be CH, CH₂ or a bond, the broken lines representoptional double bonds and R represents the substituent groups of FormulaI (R₁, R₂, R₃, R₄ and/or T) not used to create the fourth ring.

What is claimed is:
 1. A pharmaceutical composition for inhibitingmammalian leukotriene biosynthesis or action containing apharmaceutically acceptable carrier and an effective amount of acompound of the formula:

    ______________________________________                                         ##STR9##                                                                     wherein the substituents are:                                                 Y    R.sub.a   R.sub.b   R.sub.c R.sub.d                                                                           R.sub.e                                                                              R.sub.f                                                                          R.sub.g                        ______________________________________                                        S    H         SCH.sub.3 H       H   H      H  H                              S    H         H         SCF.sub.3                                                                             H   H      H  H                              S    H         H         CHO     H   H      H  H                              S    H         H         COCF.sub.3                                                                            H   H      H  H                              S    H         H         H       H   SCH.sub.3                                                                            H  H                              S    H         H         H       H   CO.sub.2 CH.sub.3                                                                    H  H                              S    H         H         H       H   CO.sub.2 H                                                                           H  H                              S    H         H         H       H   CHO    H  H                              S    H         H         H       H   CONH.sub.2                                                                           H  H                              S    H         H         H       H   CH.sub.2 OH                                                                          H  H                              S    H         H         Cl      H   Co.sub.2 Me                                                                          H  H                              S    H         H         Cl      H   CO.sub.2 H                                                                           H  H                              S    H         H         Cl      H   CHO    H  H                              S    H         H         Cl      H   COHN.sub.2                                                                           H  H                              S    H         H         Cl      H   CH.sub.2 OH                                                                          H  H                              S    H         Obenzyl   Cl      H   H      H  H                              S    H         OEt       Cl      H   F      H  H                              S    H         OEt       Cl      H   CH.sub.3                                                                             H  H                              S    CH.sub.3  H         Cl      H   CH.sub.3                                                                             H  H                              S    H         CH.sub.3  Cl      H   CH.sub.3                                                                             H  H                              S    H         OMe       Br      H   OMe    H  H                              S    H         OMe       Cl      H   OMe    H  H                              S    H         OEt       Br      H   OEt    H  H                              S    H         OEt       Cl      H   OEt    H  H                              S    H         OMe       Cl      H   OEt    H  H                              S    H         OMe       H       H   SMe    H  H                              O    H         OMe       Br      H   OMe    H  H                              O    H         OMe       Cl      H   OMe    H  H                              S    H         OMe       Br      H   Me     H  H                              SO.sub.2                                                                           H         H         OH      H   H      H  H                              SO.sub.2                                                                           H         OMe       OH      H   OMe    H  H                              SO.sub.2                                                                           OMe       OMe       Me      H   H      H  H                              SO.sub.2                                                                           H         H         OMe     H   H      H  H                              SO.sub.2                                                                           H         OMe       OMe     H   OMe    H  H                              S    OCH.sub.3 OCH.sub.3 Me      H   H      H  H                              S    H         H         COCH.sub.3                                                                            H   H      H  H                              S    OCH.sub.3 H         Br      H   OCH.sub.3                                                                            H  H                              S    OCH.sub.3 Cl        Cl      H   OCH.sub.3                                                                            H  H                              S    OCH.sub.3 H         Cl      H   OCH.sub.3                                                                            H  H                              S    H                                                                                        ##STR10##                                                                              H       H   OCH.sub.3                                                                            H  H                              S    H                                                                                        ##STR11##                                                                              Br      H   OCH.sub.3                                                                            H  H                              SO.sub.2                                                                           H         OCH.sub.3 OH      H   OCH.sub.3                                                                            H  H                              SO.sub.2                                                                           NHPr      H         NHPr    H   H      H  H                              SO.sub.2                                                                            ##STR12##                                                                              H                                                                                        ##STR13##                                                                            H   H      H  H                              SO.sub.2                                                                           H         OCH.sub.3                                                                                ##STR14##                                                                            H   OCH.sub.3                                                                            H  H                              SO.sub.2                                                                           H         OCH.sub.3 Br      H   OCH.sub.3                                                                            H  H                              S    NHPr      H         NHPr    H   H      H  H                              S    NHPr      H         NHPr    H   OCH.sub.3                                                                            H  H                              S    H         NHPr      NHPr    H   H      H  H                              S    H         NHPr      NHPr    H   OCH.sub.3                                                                            H  H                              S    H         OCH.sub.3 NH.sub.2                                                                              H   OCH.sub.3                                                                            H  H                              S    H         OCH.sub.3 NHPr    H   OCH.sub.3                                                                            H  H                              SO.sub.2                                                                           H         OCH.sub.3 NHPr    H   OCH.sub.3                                                                            H  H                              O    OCH.sub.3 H         Cl      H   OCH.sub.3                                                                            H  H                              O    OCH.sub.3 H         Br      H   OCH.sub.3                                                                            H  H                              O    NHPr      H         NHPr    H   H      H  H                              SO.sub.2                                                                           H         OCH.sub.3 CN      H   OCH.sub.3                                                                            H  H                              SO.sub.2                                                                           H        OCH.sub.3                                                                              NHCH.sub.2 CO.sub.2 R                                                                   H   OCH.sub.3                                                                            H  H                              SO.sub.2                                                                           H         OCH.sub.3 Sn-Bu   H   OCH.sub.3                                                                            H  H                              SO.sub.2                                                                           H         OCH.sub.3 CH.sub.2 CO.sub.2 R                                                                   H   OCH.sub.3                                                                            H  H                              SO.sub.2                                                                           H         OCH.sub.3 SO.sub.2 CH.sub.3                                                                     H   OCH.sub.3                                                                            H  H                              S    H         Sn-Bu     H       H   H      H  H                              S    H         H         Sn-Bu   H   H      H  H                              S    H         CH.sub.3  Sn-Bu   H   H      H  H                              S    H         OMe       Br      H   CF.sub.3                                                                             H  H                              S    H         OMe       Br      H   F      H  H                              S    H         OMe       Br      H   Cl     H  H                              S    H         OMe       Br      H   Br     H  H                              S    H         OMe       Br      H   NMe.sub.2                                                                            H  H                              S    H         OMe       Br      H   SMe    H  H                              S    H         OMe       Br      H   SO.sub.2 Me                                                                          H  H                              S    H         OMe       Br      H   Ph     H  H                              ______________________________________                                         and R is H or C.sub.2 to C.sub.4 alkyl.                                  


2. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y     R.sub.a  R.sub.b R.sub.c                                                                           R.sub.d                                                                              R.sub.e                                                                              R.sub.f                                                                           R.sub.g                          ______________________________________                                        S     H        OMe     Br  H      OMe    H   H                                S     H        OMe     Cl  H      OMe    H   H                                S     H        OEt     Br  H      OEt    H   H                                S     H        OEt     Cl  H      OEt    H   H                                S     H        OMe     Cl  H      OEt    H   H.                               ______________________________________                                    


3. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y     R.sub.a   R.sub.b                                                                             R.sub.c                                                                             R.sub.d                                                                           R.sub.e R.sub.f                                                                           R.sub.g                           ______________________________________                                        S     OCH.sub.3 H     Br    H   OCH.sub.3                                                                             H   H                                 S     OCH.sub.3 Cl    Cl    H   OCH.sub.3                                                                             H   H                                 S     OCH.sub.3 H     Cl    H   OCH.sub.3                                                                             H   H.                                ______________________________________                                    


4. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y     R.sub.a  R.sub.b R.sub.c                                                                           R.sub.d                                                                              R.sub.e                                                                              R.sub.f                                                                           R.sub.g                          ______________________________________                                        O     H        OMe     Br  H      OMe    H   H                                O     H        OMe     Cl  H      OMe    H   H.                               ______________________________________                                    


5. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y     R.sub.a   R.sub.b                                                                             R.sub.c                                                                             R.sub.d                                                                           R.sub.e R.sub.f                                                                           R.sub.g                           ______________________________________                                        O     OCH.sub.3 H     Cl    H   OCH.sub.3                                                                             H   H                                 O     OCH.sub.3 H     Br    H   OCH.sub.3                                                                             H   H.                                ______________________________________                                    


6. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y   R.sub.a                                                                              R.sub.b   R.sub.c                                                                              R.sub.d                                                                             R.sub.e                                                                              R.sub.f                                                                           R.sub.g                          ______________________________________                                        S   H      SCH.sub.3 H      H     H      H   H                                S   H      H         H      H     SCH.sub.3                                                                            H   H                                S   H      OMe       H      H     SMe    H   H                                S   H      S--n-Bu   H      H     H      H   H                                S   H      H         S--n-Bu                                                                              H     H      H   H                                S   H      CH.sub.3  S--n-Bu                                                                              H     H      H   H                                S   H      OMe       Br     H     SMe    H   H                                S   H      OMe       Br     H     SO.sub.2 Me                                                                          H   H.                               ______________________________________                                    


7. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y    R.sub.a                                                                             R.sub.b  R.sub.c R.sub.d                                                                             R.sub.e                                                                              R.sub.f                                                                             R.sub.g                        ______________________________________                                        S    H     H        H       H     CO.sub.2 CH.sub.3                                                                    H     H                              S    H     H        H       H     CO.sub.2 H                                                                           H     H                              S    H     H        H       H     CONH.sub.2                                                                           H     H                              S    H     H        Cl      H     CO.sub.2 Me                                                                          H     H                              S    H     H        Cl      H     CO.sub.2 H                                                                           H     H                              S    H     H        Cl      H     CONH.sub.2                                                                           H     H                              SO.sub.2                                                                           H     OCH.sub.3                                                                              CH.sub.2 CO.sub.2 R                                                                   H     OCH.sub.3                                                                            H     H.                             ______________________________________                                    


8. A composition of claim 1 wherein the substituents are:

    __________________________________________________________________________    Y  R.sub.a    R.sub.b    R.sub.c   R.sub.d                                                                         R.sub.e                                                                           R.sub.f                                                                         R.sub.g                            __________________________________________________________________________    S  H                                                                                         ##STR15## H         H OCH.sub.3                                                                         H H                                  S  H                                                                                         ##STR16## Br        H OCH.sub.3                                                                         H H                                  SO.sub.2                                                                          ##STR17## H                                                                                         ##STR18##                                                                              H H   H H                                  SO.sub.2                                                                         H          OCH.sub.3                                                                                 ##STR19##                                                                              H OCH.sub.3                                                                         H H                                  __________________________________________________________________________


9. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y     R.sub.a                                                                             R.sub.b  R.sub.c    R.sub.d                                                                           R.sub.e                                                                             R.sub.f                                                                            R.sub.g                        ______________________________________                                        S     H     OCH.sub.3                                                                              NH.sub.2   H   OCH.sub.3                                                                           H    H                              S     H     OCH.sub.3                                                                              NHPr       H   OCH.sub.3                                                                           H    H                              SO.sub.2                                                                            H     OCH.sub.3                                                                              NHCH.sub.2 CO.sub.2 R                                                                    H   OCH.sub.3                                                                           H    H.                             ______________________________________                                    


10. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y      R.sub.a                                                                             R.sub.b R.sub.c                                                                           R.sub.d                                                                              R.sub.e R.sub.f                                                                           R.sub.g                           ______________________________________                                        S      H     H       H   H      CHO     H   H                                 S      H     H       H   H      CH.sub.2 OH                                                                           H   H                                 S      H     H       Cl  H      CHO     H   H                                 S      H     H       Cl  H      CH.sub.2 OH                                                                           H   H.                                ______________________________________                                    


11. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y   R.sub.a  R.sub.b  R.sub.c                                                                             R.sub.d                                                                             R.sub.e                                                                              R.sub.f                                                                           R.sub.g                          ______________________________________                                        S   NHPr     H        NHPr  H     H      H   H                                S   NHPr     H        NHPr  H     OCH.sub.3                                                                            H   H                                S   H        NHPr     NHPr  H     H      H   H                                S   H        NHPr     NHPr  H     OCH.sub.3                                                                            H   H                                O   NHPr     H        NHPr  H     H      H   H.                               ______________________________________                                    


12. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y     R.sub.a R.sub.b R.sub.c                                                                           R.sub.d                                                                              R.sub.e                                                                              R.sub.f                                                                           R.sub.g                           ______________________________________                                        S     H       OEt     Cl  H      CH.sub.3                                                                             H   H                                 S     H       OMe     Br  H      Me     H   H                                 S     H       OMe     Br  H      CF.sub.3                                                                             H   H                                 S     H       OMe     Br  H      F      H   H                                 S     H       OMe     Br  H      Cl     H   H                                 S     H       OMe     Br  H      Br     H   H                                 S     H       OMe     Br  H      NMe.sub.2                                                                            H   H                                 S     H       OMe     Br  H      Ph     H   H.                                ______________________________________                                    


13. A composition of claim 1 wherein the substitutents are:

    ______________________________________                                        Y    R.sub.a  R.sub.b  R.sub.c R.sub.d                                                                           R.sub.e                                                                              R.sub.f                                                                           R.sub.g                         ______________________________________                                        SO.sub.2                                                                           H        H        OH      H   H      H   H                               SO.sub.2                                                                           H        OMe      OH      H   OMe    H   H                               SO.sub.2                                                                           OMe      OMe      Me      H   H      H   H                               SO.sub.2                                                                           H        H        OMe     H   H      H   H                               SO.sub.2                                                                           H        OMe      OMe     H   OMe    H   H                               SO.sub.2                                                                           NHPr     H        NHPr    H   H      H   H                               SO.sub.2                                                                           H        OCH.sub.3                                                                              Br      H   OCH.sub.3                                                                            H   H                               SO.sub.2                                                                           H        OCH.sub.3                                                                              NHPr    H   OCH.sub.3                                                                            H   H                               SO.sub.2                                                                           H        OCH.sub.3                                                                              CN      H   OCH.sub.3                                                                            H   H                               SO.sub.2                                                                           H        OCH.sub.3                                                                              S--n-Bu H   OCH.sub.3                                                                            H   H                               SO.sub.2                                                                           H        OCH.sub.3                                                                              SO.sub.2 CH.sub.3                                                                     H   OCH.sub.3                                                                            H   H.                              ______________________________________                                    


14. A composition of claim 1 wherein the substituents are:

    ______________________________________                                        Y   R.sub.a  R.sub.b    R.sub.c R.sub.d                                                                           R.sub.e                                                                             R.sub.f                                                                           R.sub.g                         ______________________________________                                        S   H        H          CHO     H   H     H   H                               S   H        H          COCF.sub.3                                                                            H   H     H   H                               S   H        O--benzyl  Cl      H   H     H   H                               S   CH.sub.3 H          Cl      H   CH.sub.3                                                                            H   H                               S   H        CH.sub.3   Cl      H   CH.sub.3                                                                            H   H                               S   OCH.sub.3                                                                              OCH.sub.3  Me      H   H     H   H                               S   H        H          COCH.sub.3                                                                            H   H     H   H.                              ______________________________________                                    


15. A composition of claim 1 wherein the compound is:4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one.
 16. A composition of claim1 wherein the compound is: 4-chloro-2,7-dimethoxy-3H-phenothiazin-3-one.17. A composition of claim 1 wherein the compound is:4-bromo-2,7-diethoxy-3H-phenothiazin-3-one.
 18. A composition of claim 1wherein the compound is: 4-chloro-2,7-diethoxy-3H-phenothiazin-3-one.19. A composition of claim 1 wherein the compound is:4-bromo-2,7-dimethoxy-3H-phenoxazin-3-one.
 20. A composition of claim 1wherein the compound is: 4-chloro-2,7-dimethoxy-3H-phenoxazin-3-one. 21.A pharmaceutical composition for inhibiting mammalian luekotrinebiosynthesis or action containing a pharmaceutically acceptable carrierand an effective amount of a compound of the formula:

    ______________________________________                                         ##STR20##                                                                    wherein the substituents are:                                                 R.sub.a R.sub.b        R.sub.c                                                                              R.sub.d                                         ______________________________________                                        t-Bu    t-Bu           H      H                                               t-Bu    t-Bu           F      H                                               t-Bu    t-Bu           Me     H                                               t-Bu    t-Bu           SMe    H                                               t-Bu    t-Bu           H      OMe                                             ______________________________________                                    


22. 2-S-glutathionyl-3H-phenothiazin-3-one; or4-chloro-2-S-glutathionyl-phenothiazin-3-one.
 23. A pharmaceuticalcomposition for inhibiting mammalian luekotrine biosynthesis or actioncontaining a pharmaceutically acceptable carrier and an effective amountof a compound of the formula:

    ______________________________________                                         ##STR21##                                                                    wherein the substituents are:                                                 Y           R.sub.1          R.sub.2                                          ______________________________________                                        S, SO, or SO.sub.2                                                                        2-Cl             H                                                "           2-SCF.sub.3      H                                                             ##STR22##       H                                                S           2-t-Bu           4-t-Bu                                           S, SO, or SO.sub.2                                                                        2-CN             H                                                "           H                3-CO.sub.2 Et                                    "           H                3-Cl                                             "           H                H                                                "           H                H                                                "           2-Cl             H                                                S           H                H                                                S           2-Cl             3-Cl                                             S           2-Br             3-Br                                             S           H                H                                                S           2-Cl             H                                                S           2-F              H                                                S           2-Br             H                                                S           2-CF.sub.3       H                                                S           2-SCF.sub.3      H                                                S           2-SO.sub.2 CF.sub.3                                                                            H                                                S           H                3-Cl                                             S           H                3-CO.sub.2 Et                                    S           H                3-CO.sub.2 H                                     S           H                3-CN                                             S           H                3-SCF.sub.3                                      S           H                H                                                S           H                H                                                S           2-Br             H                                                S           2-Cl             H                                                S           2-Cl             H                                                S           2-Cl             H                                                S           2-Cl             H                                                S           2-Cl             H                                                S           H                3-CONMe.sub.2                                    S           2-Cl             H                                                S                                                                                          ##STR23##       H                                                S           2-SO.sub.2 CH.sub.3                                                                            H                                                S           2-CH.sub.2 CHCH.sub.2                                                                          H                                                S           H                3-N(CH.sub.3).sub.2                              S           H                H                                                S           2-CH.sub.2 CO.sub.2 H                                                                          H                                                S           2-Cl             H                                                S           2-COCH.sub.3     H                                                S           H                H                                                S           H                H                                                S           2-COCH.sub.3 H                                                    S           H                H                                                S           4-Cl             H                                                SO          H                H                                                SO.sub.2    H                H                                                SO.sub.2    4-Cl             H                                                S           2-t-Bu           9-t-Bu                                           S           2-t-Bu           7-t-Bu                                           S           2-t-Bu           7-t-Bu                                           S           2-t-Bu           7-t-Bu                                           ______________________________________                                        R.sub.3          R.sub.4   T                                                  ______________________________________                                        H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  4-Cl             H         H                                                  4-SO.sub.2 CH.sub.3                                                                            H         H                                                  4-Cl             H         H                                                  H                H         H                                                  4-Cl             7-Cl      9-Cl                                               4-Br             7-Br      9-Br                                               H                7-SO.sub.2 CH.sub.3                                                                     H                                                  4-SO.sub.2 CH.sub.3                                                                            H         H                                                  4-Cl             H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  4-Cl             H         H                                                  4-SCF.sub.3      H         H                                                  4-Br             H         H                                                  H                8-CN      H                                                  H                8-CO.sub.2 Et                                                                           H                                                  H                8-CO.sub.2 H                                                                            H                                                  H                8-CF.sub.3                                                                              H                                                  H                7-SO.sub.2 CH.sub.3                                                                     H                                                  H                H         H                                                  H                7-OCH.sub.3                                                                             H                                                  H                H         H                                                  H                H         H                                                  4-CH.sub.2 CHCH.sub.2                                                                          H         H                                                  H                H         H                                                  4-Cl             7-SC.sub.6 H.sub.5                                                                      H                                                  H                H         H                                                  4-SCH.sub.2 CO.sub.2 H                                                                         H         H                                                  H                H         7-CF.sub.3                                         4-COC.sub.6 H.sub.5                                                                            H         7-CF.sub.3                                         H                H         H                                                  H                7-OCH.sub.3                                                                             H                                                  4-COC.sub.6 H.sub.5                                                                            7-OCH.sub.3                                                                             H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  H                H         H                                                  4-OMe            H         H                                                  4-F              H         H                                                  4-Me             H         H                                                  4-SMe            H         H                                                  ______________________________________                                    


24. A pharmaceutical composition for inhibiting mammalian luekotrinebiosynthesis or action containing a pharmaceutically acceptable carrierand an effective amount of a compound of the formula:

    __________________________________________________________________________     ##STR24##                                                                    wherein the substituents are                                                  R.sub.1   R.sub.2   R.sub.3 R.sub.4                                                                             T                                           __________________________________________________________________________    2-N(Me).sub.2                                                                           H         H       H     H                                           2-SMe     H         H       H     H                                           2-SpPAA   H         H       H     H                                           2-C(O)CH.sub.3                                                                          H         H       H     H                                           H         2-SO.sub.3 H                                                                            H       H     H                                           H         H         7-OH    6-propyl                                                                            H                                           4-Cl      1-CH.sub.2 COOH                                                                         H       H     H                                           4-Cl      2-CH.sub.2 COOH                                                                         H       H     H                                           4-OH      2-OMe     7-OMe   H     H                                           4-Me      1-OMe     2-OMe   H     H                                           4-Cl      H         6-CH.sub.2 COOH                                                                       H     H                                           4-Cl      H         7-CH.sub.2 COOH                                                                       H     H                                           4-Cl      H         8-CH.sub.2 COOH                                                                       H     H                                           4-Cl      2-N(Me).sub.2                                                                           H       H     H                                           4-Cl      1-N(Me).sub.2                                                                           H       H     H                                           4-Cl      2-N(Me).sub.2                                                                           7-OMe   H     H                                           4-Cl      2-N(Me).sub.2                                                                           7-Cl    H     H                                           4-Cl      2-SMe     H       H     H                                           4-Cl      2-SCH.sub.2 COOH                                                                        H       H     H                                           4-Cl      2-SpPAA   H       H     H                                           4-Cl      1-SpPAA   H       H     H                                           4-Cl      2-SpPAA   7-OMe   H     H                                           4-Cl      2-SO.sub.3 H                                                                            H       H     H                                           4-Cl      2-OMe     7-Cl    H     H                                           4-OMe     2-SMe     H       H     H                                           4-SMe     H         H       H     H                                           4-Cl      H         7/8-(CH.sub.2).sub.4                                                                        H                                           4-Cl      H         7/8-(CH.sub.2).sub.3                                                                        H                                           4-Br      2-OMe     7-OMe   H     H                                           7-NH.sub.2                                                                              H         H       H     H                                           2-Me      7-N(Me).sub.2                                                                           H       H     H                                           7-N(Me).sub.2                                                                           H         H       H     H                                           1-CO.sub.2 H                                                                            4-OH      7-NMe.sub.2                                                                           H     H                                           1-Me      7-Me      H       H     4-Cl                                        2-Me      7-Me      H       H     4-Cl                                        1-OMe     2-OMe     7-Me    H     H                                           2-OMe     7-SMe     H       H     H                                           4-COMe    H         H       H     H                                           2 n-Bu    H         H       H     H                                           4-Sn-Bu   H         H       H     H                                           2-Me      4-Sn-Bu   H       H     H                                           1-OMe     2-OMe     4-Me    H     H                                           1-OMe     7-OMe     H       H     4-Br                                        1-OMe     7-OMe     2-Cl    H     4-Cl                                        1-OMe     7-OMe     H       H     4-Cl                                         ##STR25##                                                                              7-OMe     H       H     H                                            ##STR26##                                                                              7-OMe     H       H     4-Br                                        2-OMe     4-OH      7-OMe   H     H                                           1-NHPr    4-NHPr    H       H     H                                            ##STR27##                                                                               ##STR28##                                                                              H       H     H                                           4-COMe    H         H       H     H                                           2-NHPr    4-NHPr    H       H     H                                           2-OME     4-CN      7-OMe   H     H                                           2-OMe                                                                                    ##STR29##                                                                              7-OMe   H     H                                           2-OMe     4-NHPr    7-OMe   H     H                                           1-NHPr    4-NHPr    H       H     H                                           1-NHPr    4-NHPr    7-OMe   H     H                                           2-NHPr    4-NHPr    7-OMe   H     H                                           2-OMe     4-NH.sub.2                                                                              7-OMe   H     H                                           2-OMe     4-NHPr    7-OMe   H     H                                           1-OMe     4-Cl      7-OMe   H     H                                           1-OMe     4-Br      7-OMe   H     H                                           1-OMe     4-CN      7-OMe   H     H                                           2-OMe     4-NHCH.sub.2 CO.sub.2 R                                                                 7-OMe   H     H                                           2-OMe     4-Sn-Bu   7-OMe   H     H                                           2-OMe     4-CH.sub.2 CO.sub.2 R                                                                   7-OMe   H     H                                           2-OMe     4-SO.sub.2 Me                                                                           7-OMe   H     H                                           2-Sn-Bu   H         H       H     H                                           4-Sn-Bu   H         H       H     H                                           2-Me      4-Sn-Bu   H       H     H                                           2-OMe     7-Me      H       H     4-Br                                        2-OMe     7-CF.sub.3                                                                              H       H     4-Br                                        2-OMe     7-F       H       H     4-Br                                        2-OMe     7-Cl      H       H     4-Br                                        2-OMe     7-Br      H       H     4-Br                                        2-OMe     7-NMe.sub.2                                                                             H       H     4-Br                                        2-OMe     7-SMe     H       H     4-Br                                        2-OMe     7-SO.sub.2 Me                                                                           H       H     4-Br                                        2-OMe     7-Ph      H       H     4-Br                                        1-Me      7-Me      H       H     4-Cl                                        2-NH.sub.2                                                                              H         H       H     H                                           __________________________________________________________________________

where Y is S, SO, or So₂ ; pPAA is paraphenylacetic acid; and R is H orC₁ to C₄ alkyl.
 25. A pharmaceutical composition for inhibitingmammalian luekotrine biosynthesis or action containing apharmaceutically acceptable carrier and an effective amount of acompound of the formula:

    ______________________________________                                         ##STR30##                                                                    wherein the substituents are:                                                 R.sub.1    R.sub.2   R.sub.3 R.sub.4 T                                        ______________________________________                                        2-OMe      7-OMe     H       H       1-Br                                     1-OMe      7-OMe     H       H       2-Br                                     1-OMe      7-OMe     H       H       4-Br                                     1-OMe      7-OMe     H       H       2-Cl                                     1-OMe      7-OMe     H       H       4-Cl                                     2-OMe      7-OMe     H       H       1-Cl                                     2-OMe      7-OMe     H       H       4-Cl                                     2-OEt      7-OEt     H       H       1-Br                                     2-OEt      7-OEt     H       H       4-Br                                     2-OEt      7-OEt     H       H       1-Cl                                     2-OEt      7-OEt     H       H       4-Cl                                     2-OMe      7-OMe     8-OMe   H       1-Br                                     2-OMe      7-OMe     8-OMe   H       4-Br                                     2-OMe      7-OMe     H       H       4-F                                      2-OMe      7-OMe     H       H       4-CF.sub.3                               2-OMe      7-OEt     H       H       4-Br                                     2-OMe      7-OEt     H       H       4-Cl                                     2-OMe      7-OEt     H       H       4-F                                      2-OMe      7-OEt     H       H       4-CF.sub.3                               2-OEt      7-OMe     H       H       4-Br                                     2-OEt      7-OMe     H       H       4-Cl                                     2-OEt      7-OMe     H       H       4-F                                      2-OEt      7-OMe     H       H       4-CF.sub.3                               2-OMe      7-OMe     H       H       4-Br                                     ______________________________________                                    